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Molecular medicine reports

Molecular medicine reports

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NLRP3 deficiency protects against acetaminophen?induced liver injury by inhibiting hepatocyte pyroptosis

Published:1 April 2024 DOI: 10.3892/mmr.2024.13185 PMID: 38391117
Xinying Yuan,?Peng Chen,?Xiaoyu Luan,?Chaoqun Yu,?Longyu Miao,?Yaru Zuo,?Anxu Liu,?Tianyi Sun,?Guohu Di

Abstract

Acetaminophen (APAP) overdose is the primary cause of drug?induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP?induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase?1, IL?1β, GSDMD and Caspase?3), western blotting (NLRP3, Caspase?1, IL?1β, GSDMD and Caspase?3) and RT?qPCR (NLRP3, Caspase?1 and IL?1β) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL?6, IL?18, IL?1β and TNF?α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT?qPCR (TNF?α, Il?6, Mcp?1, Cxcl?1, Cxcl?2). A Cell Counting Kit?8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT?qPCR (CyclinA2, CyclinD1 and CyclinE1). Through investigation of an APAP?induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both in?vivo and in?vitro. Additionally, mice with hepatocyte?specific knockout of Nlrp3 exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte Nlrp3 deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP?induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Disulfiram 97-77-8 C10H20N2S4 579 suppliers $13.44-$1504.50
Disulfiram 97-77-8 C10H20N2S4 579 suppliers $13.44-$1504.50
Disulfiram 97-77-8 C10H20N2S4 579 suppliers $13.44-$1504.50
Disulfiram 97-77-8 C10H20N2S4 579 suppliers $13.44-$1504.50
MCC950 210826-40-7 C20H24N2O5S 138 suppliers $44.00-$1641.00
MCC950 210826-40-7 C20H24N2O5S 138 suppliers $44.00-$1641.00
MCC950 210826-40-7 C20H24N2O5S 138 suppliers $44.00-$1641.00
MCC950 210826-40-7 C20H24N2O5S 138 suppliers $44.00-$1641.00

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